Project Summary Treatment resistant depression (TRD) is a major cause of distress and disability. The discovery of the antidepressant effects of ketamine, an N -Methyl- D -aspartate glutamate receptor (NMDAR) antagonist, has brought new hope to TRD patients. The search for the biological bases underlying the antidepressant effects of ketamine is a key priority. Preclinical studies suggest that, in the subcallosal cortex (SCC), ketamine activates cortical circuits, increasing glutamate release, stimulating α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR), and engaging downstream neuroplasticity mechanisms. In animal models of depression, AMPAR blockade prevents the antidepressant effects of ketamine. However, it is unclear whether this applies to humans with TRD. With the availability of the first FDA-approved AMPAR antagonist, perampanel, we can now test this hypothesis. Aim 1 evaluates whether perampanel pretreatment prevents the reduction in depression symptoms produced by ketamine in TRD patients. Aim 2 tests whether perampanel pretreatment augments ketamine-related increases in SCC resting state functional connectivity. Aim 3 assesses whether perampanel blocks ketamine-associated increases in SCC cerebral metabolic rate of oxygen relative to the pre-ketamine baseline. These metabolic increases may subserve restoring synaptic connectivity in TRD patients. Together these aims would provide an important test of a central hypothesis related to the mechanism underlying the therapeutic effects of ketamine and could inform efforts to develop alternatives to ketamine as a treatment for TRD.